1、沙利度胺(Thd)在多发性骨髓瘤中的应用,抗肿瘤专业,主要内容,1954首先在前联邦德国合成。1956德国上市,镇静及预防妊娠性呕吐1960海豹儿1961全世界市场召回及禁止上市1963正式退市1965发现反应停可以有效地减轻麻风性皮肤结节红斑的患者的皮肤症状1991发现其抑制 TNF-抗炎作用1994发现其抗血管新生抗肿瘤作用,研发历史,沙力度胺的抗肿瘤作用机制:1.抑制血管生成: 抑制肿瘤和骨髓基质细胞中碱性成纤维细胞生长因子bFGF和血管内皮生长因子VEGF的分泌,从而抑制肿瘤血管新生。2.降低肿瘤坏死因子( TNF- ) 增加TNF- mRNA降解Thd TNF- 抑制NF-kB产生
2、IL-63.免疫调节:激活T淋巴细胞、自然杀伤细胞,移植候选者主要治疗方案: VTD硼替佐米/沙利度胺/地塞米松(1类推荐)非移植候选者主要治疗方案: MPT马法兰/强的松/沙利度胺(1类推荐)维持治疗: 沙利度胺(1类推荐),多发性骨髓瘤NCCN指南(2014),方法:计算机检索中国期刊全文数据库(1979-2008) 中国生物医学文献数据库(1979-2008) 中文科技期刊全文数据库(1989-2008) 并手工检索 所有纳入文献的参考文献 纳入沙利度胺治疗多发性骨髓瘤的随机对照试验 (RCT),共9个,324例患者 采用 RevMan 4.3 软件进行 Meta 分析 朱珂等.中国循证
3、医学杂志 2009,9(8):899-903,国内沙利度胺治疗多发性骨髓瘤疗效与安全性的Meta分析 (2009),研究对象:初治或复发的难治性多发性骨髓瘤患者干预措施: Thd联合MP VS MP方案 Thd联合VAD VS VAD方案观察指标:总有效率、 缓解率、副作用注: MP( 马法兰+ 泼尼松) VAD (长春新碱+阿霉素+地塞米松),纳入标准:,分析结果,从缓解率和总有效率分析,沙利度胺 +MP方案及 沙利度胺+VAD方案治疗多发性骨髓瘤明显优于单用 MP 方案及V A D 方案。从不良反应分析:主要有嗜睡、便秘、腹胀、下肢水肿 、白细胞减少及头晕乏力等。不良反应主要集中在沙利度胺
4、联合化疗组,多数文献报道这些不 良反应患者能够耐受,通过对症处理后,症状消失,不影响治疗。但因对照组不良反应数据不全,未能进行合并分析。,结论:,To provide a denitive estimate of the survival benets of MPT over MP, if any,we performed an individual patient meta-analysis based on data from all 6 completed trials. This analysis,based on individual data from 1685 patients,
5、also allows us to explore possible reasons for the heterogeneity in the reported results of the separate studies,including the impact of interactions of patient characteristics with treatment.评价指标:OS总生存期 PFS无疾病进展时间 age年龄 creatinine肌酐 2-MG albumin白蛋白 LDH乳酸脱氢酶,Thalidomide for previously untreated elde
6、rly patients with multiple myeloma:meta-analysis of 1685 individual patient data from 6 randomized clinical trials,BLOOD,4 AUGUST 2011 .VOLUME118,NUMBER 5,Thalidomide for previously untreated elderly patients with multiple myeloma:meta-analysis of 1685 individual patient data from 6 randomized clini
7、cal trials,Results:,Talidomide became a new therapeutic approach but use of Talidomide as a single agent or combination with steroids or chemotherapy is associated with several side efects like deep vein thrombosis (DVT), peripheral neuropathy (PN), constipation, somnolence, pyrexia, pain, fatigue o
8、steonecrosis of jaw, and teratogenicity that is the most worrying adverse event.,Adverse Efects of Thalidomide Administration, in Patients with Myeloma Multiplex?(2014),Mater Sociomed. 2014 Apr; 26(2): 134-136,方法:将80例(43男+37女,31-81岁)患者分成五个治疗组: 1.CTD(沙力度胺+地塞米松+环磷酰胺) 4周期 2.MPT(沙力度胺+地塞米松+马法兰) 4周期 3.大剂量
9、化疗+TD维持 4.CTD(沙力度胺+地塞米松+环磷酰胺) 5周期 5.TD每15天检测DVT和PN的发生率,Results:Our study of patients presents eight patients ( or 10% ) developed DVT. Twentyone patients (or 26.25%) developed PN.,Adverse Efects of Thalidomide Administration, in Patients with Myeloma Multiplex?(2014),Mater Sociomed. 2014 Apr; 26(2):
10、 134-136,PN and Talidomide, the lack of correlation between cumulative dose and outcome.Patients treated with thalidomide have an increased risk of DVT, antiaggregation therapy of Aspirin should be taken,Action should be taken to minimize all modif-able risk factors for thromboemboling events (e.g.
11、smoking, hypertension and hyperlipidemia),Adverse Efects of Thalidomide Administration, in Patients with Myeloma Multiplex?(2014),PeterM.Fayers,AntonioPalumbo,et al. Thalidomide for previously untreated elderly patients with multiple myeloma:meta-analysis of 1685 individual patient data from 6 rando
12、mized clinical trials . BLOOD,4 AUGUST 2011 .VOLUME118,NUMBER 5.PalumboA,FaconT,SonneveldP,et al.Thalidomide for treatment of multiplemyeloma:10years later. Blood. 2008;111(8):3968-3977.Svetlana Balkanov Krstevska,et al. Adverse Efects of Thalidomide Administration, in Patients with Myeloma Multiple
13、x? Mater Sociomed. 2014 Apr; 26(2): 134-136.李勇华等,含沙利度胺方案治疗多发性骨髓瘤 110例临床分析 J.国际输血及血液学杂志. 2007,30(300-304).朱珂等,国内沙利度胺治疗多发性骨髓瘤疗效与安全性的Meta分析 J.中国循证医学杂志2009,9(8):899-903.臧红梅等,沙利度胺的最新研究进展 . Progress in Pharmaceutical Sciences,2007,Vol.32,No.1(21-27).陈立慧等,沙利度胺及其衍生物I 临床及作用机制研究进展. Chinese Journal of New Drugs. 2006, Vo1.15 No.14(1141-1145).,参考文献:,沙利度胺治疗 MM 取得了良好的疗效,其既针对瘤细胞又针对微环境,为骨髓瘤的治疗提供了新的方法沙利度胺治疗 MM还存在一些问题有待解决, 如其对MM 的作用机制还未完全明确 ,其对 MM 基因的影响到底如何,它的量效关系、最低有效剂量、 维持时间、最佳方案、不良反应如何减少以及其引起血栓形成的确切机制等均需进一步的探讨。用药监护:监测大小便、PN、凝血功能等,及时干预。,总结:,敬请批评指正!,